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Equfina, Known as Xadago in US, Approved in S. Korea as Levodopa Add-on

therapy approval

Equfina (safinamide) has been approved in South Korea as an add-on therapy to levodopa for Parkinson’s disease patients who experience “off” episodes, Eisai, which is marketing this medication in parts of Asia, announced.

The approval makes South Korea the first country in Asia outside of Japan to sell Equfina.

Under the brand name Xadago, the add-on therapy was approved for the same indication in Europe in 2015 and in the U.S. in 2017. In Canada it is marketed under the name Onstryv.

“Off” periods in Parkinson’s are characterized by the reappearance or worsening of motor symptoms — such as tremors and dyskinesia (involuntary movements) — due to a gradual decline in levodopa’s effectiveness throughout the day.

Safinamide, developed by Newron Pharmaceuticals, increases the level and function of dopamine — the neurotransmitter, or signaling molecule, missing in those with Parkinson’s — in the brain. It does so by inhibiting the enzyme monoamine oxidase B that normally breaks down dopamine, and also by inhibiting (blocking) transporters that are responsible for its uptake, meaning its absorption and retention.

Safinamide also inhibits an excessive release of the neurotransmitter glutamate.

Equfina’s approval in South Korea was based on clinical results from the SETTLE Phase 3 study (NCT00627640). The global trial enrolled 549 patients experiencing off episodes while on a stable regimen of levodopa plus benserazide or Lodosyn (carbidopa).

Participants were randomized to either oral safinamide (50 mg per day, increased to 100 mg per day if tolerated) or a placebo as an add-on therapy for 24 weeks.

The study’s main goal was changes in mean daily “on” time (the period in which motor symptoms are efficiently controlled) about six months of treatment or placebo use.

Results showed that adding safinamide to levodopa significantly increased the length of “on” periods without dyskinesia by almost one hour (57.6 minutes) compared with placebo.

Adverse treatment reactions were seen in 28.5% of patients in the safinamide group and in 27.6% of those given a placebo, with the most frequent including dyskinesia, nausea, and somnolence (sleepiness).

Newron entered a licensing agreement with Meiji in 2011, granting the company exclusive rights to manufacture and commercialize safinamide in Asia. Based on a licensing agreement between Eisai and Meiji, Eisai now has exclusive rights for developing and marketing safinamide in much of Asia.

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Fluorescent-based Method May Help Measure Levels of Levopoda in Blood

Fluorescent test

The levels of levodopa, one of the gold-standard treatments in Parkinson’s disease, may be assessed using a fast, simple, low-cost, fluorescent-based method, a new study suggests.

The study, “Blue and green emission-transformed fluorescent copolymer: Specific detection of levodopa of anti-Parkinson drug in human serum,” was published in the journal Talanta.

Parkinson’s disease is a central nervous system disorder characterized by low levels of the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate and, among other functions, helps regulate movement.

Treatment with levopoda, or L-DOPA — a precursor to dopamine — has long been one of the gold standards for Parkinson’s. However, it is important to regulate and monitor the levels of levopoda in patients to prevent undesirable side effects.

Now, a team of Chinese researchers developed a fast and simple method to measure the levels of levopoda in patients’ blood. Specifically, the method consists of mixing levopoda with a chemical solution called PEI, which results in a blue fluorescence within 10 minutes and its conversion to green fluorescence within two hours, at which time the mix is analyzed using a fluorescence spectrophotometer that emits light of a certain wavelength.

Researchers tested if the conversion in fluorescence from blue to green was highly specific for levodopa throughout time. This method was highly selective and sensitive to determine the presence of levodopa within a specific concentration rage (0 to 50 micromolar).

They then tested their method to detect levodopa in different concentrations of human diluted blood serum samples. Both fluorescence emissions showed a good correlation with levopoda levels, with the green emission showing an excellent recovery rate at the higher serum concentrations (up to 30%).

The recovery rate of a sample allows researchers to quantify the concentration of a compound present in the sample based on the fluorescence it emits.

The team then tested the method’s ability to measure the levels of levopoda present in three different levopoda-containing therapies used in Parkinson’s disease: Sinemet tablets (a controlled-release combination of levodopa and carbidopa, developed by Merck), levodopa and benserazide hydrochloride tablets (sold as Madopar or Prolopa, both by Roche), and levopoda tablets.

The results showed that both blue and green fluorescence emission correlated with the levels of levopoda, with a recovery rate ranging from 90.9% to 109.7%.

Finally, they applied their method to detect the different levodopa concentrations present in all three anti-Parkinson therapies when diluted in human blood samples. Once again, the method showed an excellent recovery of levopoda levels ranging from 91.5% to 107.4%.

Overall, “our developed dual-signal approach provided a promising platform for the diagnosis and treatment of Parkinson’s disease,” the researchers concluded.

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FDA Clears Way for Phase 2 Trial of AV-101 for Levodopa-Induced Dyskinesia

AV-101

VistaGen Therapeutics will begin a Phase 2 clinical trial to evaluate its lead candidate AV-101 as a potential treatment to reduce dyskinesia (abnormal involuntary movements) induced by levodopa in patients with Parkinson’s disease, after the U.S. Food and Drug Administration (FDA) cleared the company’s investigational new drug (IND) application.

Parkinson’s is characterized by the loss of neurons that produce the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — is one of the gold standards for Parkinson’s. However, as the disease progresses, patients need larger doses.

Dyskinesia — sudden, involuntary movement — is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s.

Amantadine (brand names Gocovri, Symmetrel, Symadine) can be used to treat dyskinesia, though it is often accompanied by side effects such as depression and cognitive impairment.

Amantadine acts on a specific part of NMDA (N-methyl-D-aspartate) receptors  — molecular structures involved in neuronal communication — in the brain, enhancing dopamine levels.  AV-101 is an oral NMDA receptor antagonist (inhibitor) that acts on a different part of the receptor.

Preclinical data from a non-human, primate model of Parkinson’s showed that AV-101 lessened dyskinesia without affecting the timing, extent, or duration of the therapeutic benefits of levodopa. Researchers observed none of the adverse effects with AV-101 often associated with amantadine, such as hallucinations, dizziness, and falls.

In a Phase 1b clinical study performed in collaboration with Baylor College of Medicine, researchers tested AV-101’s potential in seven healthy U.S. military veteran volunteers. Participants were randomly assigned a single (either high or low) dose of AV-101 (720 mg or 1440 mg) or a placebo.

The results showed that the higher dose of AV-101 could block NMDA activity, confirming the therapy’s target engagement. Moreover, both doses were well tolerated, without any adverse side effects.

“Current drug treatment options for levodopa-induced dyskinesia, or LID, may cause serious side effects, including hallucinations and sedation,” VistaGen CEO Shawn Singh said in a press release. “In all clinical studies to date, AV-101 has not been associated with any psychotomimetic [inducing psychotic alteration of behavior and personality] side effects or drug-related serious adverse events.”

“With its exceptional safety profile, recently successful preclinical studies in the leading primate model for LID, and the successful Phase 1b NMDAR target engagement clinical study conducted by Baylor College of Medicine in healthy volunteer U.S. military veterans, we are excited by AV-101’s potential as a novel therapy for LID,” Singh said.

VistaGen said it also received a notice of allowance from the U.S. Patent and Trademark Office covering to the use of AV-101 for levodopa-induced dyskinesia. The patent, once issued, will be in effect until at least 2034, the company said.

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